Chloromethyl quinoline derivatives and use thereof as analgesics

ABSTRACT

A chlorinated quinoline derivative of formula (I)    &lt;IMAGE&gt;  (I) wherein R1 is -CCl3, -CF3, -CHCl2 or -CH2Cl, R2 is hydrogen when R3 is not hydrogen, or is halogen, C1-4 alkoxy, C1-4 alkyl or R1, R3 is hydrogen when R2 is not hydrogen or is halogen, C1-4 alkyl, C1-4 alkoxy or CF3, R6 is hydrogen or halogen, X is halogen. The compounds are made by chlorination of selected compounds as disclosed and the new compounds can have antimicrobial, antifungal or analgesic effects.

FIELD OF THE INVENTION

The invention relates to new chloromethyl quinoline derivatives offormula (I) ##STR2## and the preparation thereof, wherein R¹ is a--CCl₃, --CF₃, --CHCl₂ or --CH₂ Cl group,

R² is hydrogen, halogen, C₁₋₄ alkoxy, C₁₋₄ alkyl or R¹

R³ is hydrogen or halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or CF₃

R⁶ is hydrogen or halogen,

X is halogen, preferably chlorine or bromine.

The compounds prepared according to the present invention are usefulpharmaceutical products and intermediates in the preparation ofpharmaceutical products and plant protectives.

BACKGROUND OF THE INVENTION

From the state of the art quinoline derivatives are known which arebiologically active, for example they exert an antimalarial (J. Med.Chem. 14. 1221, 1971) or antibacterial effect (British patentspecification No. 874,980). Among others these earlier references makethe development of a broadly applicable method for the preparation ofchloromethyl quinoline derivatives justified.

The method used up to now for this purpose (J. Chem. Soc. 123 2882,1923) is suitable first of all for the preparation of2-tribromo-methyl-quinoline derivatives (J. Chem. Soc. 1950 628; ibid1951 1145; ibid 1953 1369) and may be applied for 4-chloro-quinaldinederivatives with a poor yield (J. Med. Chem. 14 1221, 1971).

According to a more advantageous method for the preparation of2-trichloromethyl-4-chloro-quinoline, 4-quinaldinole was refluxed in thepresence of phosphorus pentachloride in phosphoroxy chloride whereuponthe product could be isolated from the obtained mixture by the aid ofchromatography with a moderate yield (Chem. Ph. Bull 29 1069, 1981).Having condensed ethyl-trichloro-acetyl-acetate with the appropriateaniline, 2-trichloromethyl-4-quinolinole derivatives were obtained witha moderate yield (J. Org. Chem. 31 3369, 1966); there is no knownprocess in the state of the art for the transformation of thesecompounds to 4-chloro derivatives.

A further disadvantage of the known methods besides the poor to moderateyields is the fact that they may be used only for the preparation of2-chloromethyl-quinoline derivatives and the selectivity of thereactions is not always sufficient. In certain cases the startingsubstance (e.g. the trichloro-aceto-acetic ester) is difficult to obtainand is an expensive compound.

DESCRIPTION OF THE INVENTION

The present invention is based on the recognition that the alkyl groupor groups of methyl-4-chloro-quinoline and methyl-4-oxy-quinoline may beselectively chlorinated.

For this purpose the phosphorus pentachloride or a form thereof formed"in situ" from phosphorus trichloride and chlorine gas are considered assuitable chlorinating agent.

In developing this process we surprisingly recognized that smallquantities of phosphorus pentahalides or phosphorus trihalides in thepresence of a solvent have a catalytic effect on the side-chainhalogenation performed with chlorine, accelerating the reaction andincreasing the selectivity thereof. Thus the di- and trihalogenation ofthe homoaromatic alkyl groups of quinoline becomes possible with goodyields.

The compounds of formula (I) may be prepared as follows:

(a) chlorinating a quinoline derivative of formula (II) ##STR3## whereinR², R³ and R⁶ are as defined above,

Y is halogen or a hydroxyl group,

R⁴ stands for a methyl, --CH₂ Cl or --CHCl₂ -group, or

(b) chlorinating a quinoline derivative of formula (III) ##STR4##wherein R¹, R³, R⁴, Y and R⁶ are as defined above, or

(c) chlorinating a quinoline derivative of formula (IV) ##STR5## whereinX, R², R³ are as defined above, or

(d) chlorinating a quinoline derivative of formula (V) ##STR6## whereinR² and R³ are as defined above.

In addition to the above substituents the following are mentioned in thespecification:

R⁵ which can be --CCl₃, --CHCl₂ or a --CH₂ Cl group, and

R⁷ which can be --CH₃, --CHCl₂, --CH₂ Cl or a --CF₃ group.

The meaning of R¹ to R⁷, X and Y does not change in the specificationand therefore will not be repeated.

Thus according to an advantageous procedure of the process variant (a)and (b) of the present invention, phosphorus pentachloride orphosphoroxy chloride and phosphorus pentachloride or chlorine gas orphosphoroxy chloride and chlorine gas may be used as chlorinating agent.

It depends on the desired endproducts which reaction conditions arechosen. Thus by the aid of the above procedures, the compounds offormula (VI) ##STR7## which belong under formula (I), may beadvantageously prepared if quinoline derivatives of formula (II) arechlorinated at a temperature of 70° to 140° C. in the presence ofhalogenated hydrocarbon or phosphoroxy chloride as solvent.

If compounds of formula (VII) ##STR8## which fall under formula (I), areto be prepared, a compound of formula (III) is chlorinated withphosphorus trihalide and chlorine gas preferably at a temperature of150° to 220° C. in the presence of halogenated hydrocarbon as solventoptionally under pressure.

For the above two process varients, mono-, di- or trichlorinebenzene orcarbon tetrachloride may be used as solvent.

If the desired compounds fall under the formula (VIII) ##STR9## whichbelong under formula (I), a compound of formula (IX) ##STR10## ischlorinated with phosphorus pentachloride at a temperature of 120° to150° C., preferably in the presence of halogenated hydrocarbon. In thiscase, too, it is advantageous to use the chlorinated benzenes assolvent.

According to process varient (c) of the invention, quinoline derivativesof formula (XI), ##STR11## representing a subcase of the compounds offormula (I), may be advantageously prepared. In this case a quinolinederivative of formula (IV) is reacted with aluminum chloride preferablyin the presence of a solvent as carbon disulfide, nitrobenzene oracetylchloride.

Process variant (d) according to the invention is advantageous for thepreparation of compounds of formula (XII), ##STR12## which belongs underformula (I). In this case a compound of formula (V) is reacted withphosphoroxy chloride but may be chlorinated with phosphoruspentachloride, too, at a temperature of 20° to 100° C.

According to process variant (d) quinoline derivatives of formula (XIII)##STR13## may be advantageously prepared by reacting a compound offormula (V) at a temperature of 110° to 150° C. with phosphoruspentachloride in the presence of a solvent such as a chlorinatedhydrocarbon, preferably chlorinated benzene.

The chlorinated quinoline derivatives of formula (I) are new where R¹and R³ are not simultaneously hydrogen.

The quinoline derivatives of formula (I) may be used for the synthesisof pharmaceutical products and plant-protecting agents.

The quinoline derivatives used as starting material in the reactionswere prepared by methods generally known from the state of art. Thus the2-methyl-4-oxy-quinoline derivatives were prepared by the Conrad-Limpachsynthesis modified by Hauser-Reynold (J. Am. Chem. Soc. 70 2402, 1948)while the appropriate 2-trifluoromethyl-4-quinoline was synthesized bythe method indicated by A. S. Dey; M. M. Joullie (J. Het. Chem. 2 113,1965). From this the appropriate 2-trifluoromethyl-4-halo derivativeheated in phosphoroxy halide was obtained.

SPECIFIC EXAMPLES

The details of the present process are demonstrated with the help of thefollowing examples.

EXAMPLE 1 2-Trichloromethyl-4,8-dichloroquinoline

The mixture of 1.9 g of 2-methyl-8-chloro-4-quinolinole and 9.0 g ofphosphorus pentachloride is heated in 20 ml of monochlorobenzene to 130°to 135° C. and stirred at this temperature for 2 hours. The reactionmixture is evaporated in vacuo, the residue is crystallized from 20 mlof methanol.

Yield: 2.01 g, 64.5%.

EXAMPLE 2 2-Trichloromethyl-6-methyl-4-chloroquinoline

The mixture of 1.9 g of 2,6-dimethyl-4-chloro-quinoline and 6.5 g ofphosphorus pentachloride is heated in 20 ml of phosphoroxy chloride for3 hours, then the mixture is admixed with ice water and the separatedproduct is filtered.

Yield: 2.81 g; 95.1%.

EXAMPLE 3 2-Trichloromethyl-8-trifluoromethyl-4-chloro-quinoline

14.5 g of 2-methyl-8-trifluoromethyl-4-quinolinole are refluxed in 70 mlof phosphoroxy chloride for 20 minutes under stirring. The mixture iscooled to 70° C., 10 ml of PCl₃ are added and chlorine gas is bubbledthrough the mixture at reduced pressure, the residue is treated with icewater and the separated product is filtered.

Yield: 22.1 g; 99.1%.

EXAMPLE 4 2-Monochloromethyl-8-methyl-4-chloro-quinoline and2-dichloromethyl-8-methyl-4-chloro-quinoline

The mixture of 1.9 g of 2,8-dimethyl-4-chloroquinoline and 2.1 g ofphosphorus pentachloride is refluxed in 5 ml of carbon tetrachlorideunder stirring for 2.5 hours. It is cooled to room temperature and afterstanding for a night the separated crystals are filtered. It consists ofthe starting material (30 mole %) and the hydrochloride salt of2-monochloromethyl-8-methyl-4-chloroquinoline (25 mole %). The filtrateis evaporated in vacuo, the residue is treated by column-chromatography(silica gel, eluent: cyclohexane).

In the first fraction 2-trichloromethyl-8-methyl-4-chloro-quinoline (10mole %), then 2-dichloromethyl-8-methyl-4-chloro-quinoline is eluted (23mole %). Finally 2-monochloromethyl-8-methyl-4-chloro-quinoline (10 mole%) is obtained.

EXAMPLE 5 2-Trichloromethyl-8-monochloromethyl-4-chloro-quinoline

A mixture of 1.92 g of 2,8-dimethyl-4-chloro-quinoline and 15 ml ofmonochlorobenzene and 12.5 g of phosphorus pentachloride is refluxed for100 hours under stirring. Isolation is carried out as in Example 1.

Yield: 2.3 g; 69.7%.

EXAMPLE 6 2-Trichloromethyl-4,6,8-trichloro-quinoline

24.8 g of 2-methyl-4,6,8-trichloro-quinoline are dissolved in 100 ml ofmonochlorobenzene and the mixture is heated to 80° C. 1 ml of phosphorustribromide is added and under intensive stirring chlorine gas is bubbledthrough the system and heated to 100° C. and the mixture is stirred atthis temperature for 2 hours. It is evaporated in vacuo, the residue istreated according to Example 1.

Yield: 31.1 g; 92.1%.

EXAMPLE 7 2-Trichloromethyl-8-trifluoromethyl-4-bromo-quinoline

3.4 g of 2,8-bis-(trifluoromethyl)-4-bromo-quinoline, 1.5 g of freshlysublimated aluminum-chloride are allowed to stand in 30 ml of abs.carbon disulfide for a night at room temperature. The organic phase iswashed with 50 ml of 10 percent icy hydrochloric acid, 2×50 ml of water,dried and evaporated. The residue is recrystallized from aqueousmethanol.

Yield: 3.3 g; 86.9%.

EXAMPLE 8 2-Trichloromethyl-8-dichloromethyl-4-chloro-quinoline

A mixture of 1.92 g of 2,8-dimethyl-4-chloro-quinoline and 15.0 g ofphosphorus pentachloride is kept in 100 ml of o-dichlorobenzene at atemperature of 175° C. for 4 hours. Meanwhile the phosphorus trichlorideformed in the reaction is continuously distilled off. The reactionmixture is treated as described in Example 1.

Yield: 3.1 g; 85.2%.

EXAMPLE 9 2,6-bis-(Trichloromethyl)-4-chloro-quinoline

8.66 g of 2,6-dimethyl-4-oxy-quinoline are refluxed in 30 ml ofphosphoroxy chloride for 30 minutes, the reaction mixture is cooled to70° C. and hexane is added. The precipitated2,6-dimethyl-4-chloro-quinoline hydrochloride salt crystals are filteredoff and triturated with ice acetone and carbon tetrachloride. Theobtained substance is kept over 75 g of phosphorus pentachloride at atemperature of 180° C. for 18 hours. The obtained melt is treated in theusual manner.

Yield: 9.7 g; 48.7%.

EXAMPLE 10

29.5 g of 2-trichloromethyl-6-methyl-4-chloro-quinoline are dissolved in100 ml of 1,2,4-trichlorobenzene, 0.5 ml of phosphorus tribromide isadded and under stirring the mixture is heated and when an innertemperature of 100° C. is attained a strong chlorine gas current ispassed through the reaction mixture. It is further heated to 200° C. andchlorinated at this temperature for 2 hours. The reaction mixture istreated as described in Example 12.

Yield: 36.3 g; 91.2%.

EXAMPLE 11 2,8-bis-(Trichloromethyl)-4-chloro-quinoline

233 ml of carbon tetrachloride and 80 ml of phosphorus trichloride aregiven into a stirring double-wall Hastelay-C-autoclave of a volume of 1liter. At 80° C. 55 g of chlorine gas are absorbed in the mixture, it isstirred for half an hour and 17.3 g of 2,8-dimethyl-4-quinolinole areadded. The temperature of the reaction mixture is slowly raised to 180°C. and stirred at this temperature for 24 hours. Meanwhile the innerpressure is raised to 28-29 atmospheres. The solvent is distilled offand the distillation residue is treated as described in Example 1.

Yield: 33.2 g; 83.4%.

EXAMPLE 12

47.9 g of 2,8-dimethyl-4-chloro-quinoline are heated in 200 ml of1,2,4-trichlorobenzene to 95° C. 1 ml of phosphorus tribromide is addedand chlorine gas is passed through the mixture under intensive stirring.It is allowed to heat to 130° C., kept at this temperature for 15minutes and then for further 4 hours at 200° C. The solvent is distilledoff in vacuo and the residue is crystallized from 400 ml of ethanol.

Yield: 85.6 g; 85.8%.

EXAMPLE 13 2-Trichloromethyl-4,6-dichloro-quinoline

3.0 g of 2-trichloromethyl-6-chloro-4-quinoline are refluxed in 20 ml ofphosphoroxy chloride for 3 hours. At reduced pressure the reactionmixture is evaporated, the residue is treated in the usual manner.

Yield: 2.2 g; 69.8%.

EXAMPLE 14 2-Dichloromethyl-5-methyl-3,4-dichloro-quinoline

1.73 g of 2,5-dimethyl-4-quinolinole are added to the 120°-125° C.mixture of 20 ml of monochlorobenzene and 8.8 g of phosphoruspentachloride in small portions. After the addition the mixture isstirred at this temperature still for one hour and treated as describedin Example 1.

Yield: 2.1 g; 71.2%.

EXAMPLE 15 2-Trichloromethyl-3,4,6-trichloro-quinoline

1.94 g of 2-methyl-6-chloro-4-quinolinole are reacted with 12.0 g ofphosphorus pentachloride according to Example 14.

Yield: 2.5 g; 71.4%.

EXAMPLE 16 2,2'-bis-(Trichloromethyl)-4,4'-dichloro-6,6'-biquinoline

A mixture of 1.5 g of 2,2'-dimethyl-4,4'-dichloro-6,6'-biquinoline, 9.0g of phosphorus pentachloride, 25.0 ml of monochlorobenzene is refluxedfor 1 hour. It is evaporated in vacuo, the residue is treated with 20 mlof cold methanol and crystallized.

Yield: 1.8 g; 64.3%.

    ______________________________________                                                           Method, number                                                                according to  Yield:                                       Compound           the example:  (%)                                          ______________________________________                                        17  2-Trichloromethyl-4-                                                                             1             73.4                                         chloroquinoline                                                           18  2-Trichloromethyl-4-                                                                             2             59.3                                         chloroquinoline                                                           19  2-Trichloromethyl-3,4-                                                                           15            67.1                                         dichloro-quinoline                                                        20  2-Trichloromethyl-5-                                                                             1             74.7                                         methyl-4-chloro-                                                              quinoline                                                                 21  2-Trichloromethyl-3,4-                                                                           15            61.5                                         dichloro-5-methyl-                                                            quinoline                                                                 22  2-Trichloromethyl-6-                                                                             1             57.3                                         methyl-4-chloro-                                                              quinoline                                                                 23  2-Trichloromethyl-3,4-                                                                           15            73.5                                         dichloro-6-methyl-                                                            quinoline                                                                 24  2-Dichloromethyl-3,4-                                                                            14            66.3                                         dichloro-6-methyl-                                                            quinoline                                                                 25  2-Trichloromethyl-8-                                                                             2             87.3                                         methyl-4-chloro-                                                              quinoline                                                                 26  2-Trichloromethyl-4,5-                                                                           1             81.8                                         dichloro-8-methyl-                                                            quinoline                                                                 27  2-Trichloromethyl-4,6-                                                                           1             83.9                                         dichloro-quinoline                                                        28  2-Dichloromethyl-3,4,6-                                                                          14            75.2                                         trichloro-quinoline                                                       29  2-Trichloromethyl-4,7-                                                                           1             63.4                                         dichloro-quinoline                                                        30  2-Trichloromethyl-3,4,7-                                                                         15            72.7                                         trichloro-quinoline                                                       31  2-Trichloromethyl-4,6,8-                                                                         1             70.6                                         trichloro-quinoline                                                       32  2-Trichloromethyl-4,6,8-                                                                         2             96.7                                         trichloro-quinoline                                                       33  2-Trichloromethyl-6-                                                                             1             64.3                                         methoxy-4-chloro-                                                             quinoline                                                                 34  2-Trichloromethyl-6-                                                                             2             69.9                                         methoxy-4-chloro-                                                             quinoline                                                                 35  2-Trichloromethyl-6-                                                                             15            43.5                                         methoxy-3,4-dichloro-                                                         quinoline                                                                 36  2-Trichloromethyl-8-                                                                             1             48.2                                         methoxy-4-chloro                                                              quinoline                                                                 37  2-Trichloromethyl-6-                                                                             2             94.3                                         trifluoromethyl-4-                                                            chloro-quinoline                                                          38  2-Trichloromethyl-6-                                                                             7             73.7                                         trifluoromethyl-4-                                                            chloro-quinoline                                                          39  2-Trichloromethyl-7-                                                                             2             79.8                                         trifluoromethyl-4-                                                            chloro-quinoline                                                          40  2-Trichloromethyl-7-                                                                             7             84.5                                         trifluoromethyl-4-                                                            chloro-quinoline                                                          41  2-Trichloromethyl-8-                                                                             2             87.5                                         trifluoromethyl-4-                                                            chloro-quinoline                                                          42  2-Trichloromethyl-8-                                                                             1             71.4                                         trifluoromethyl-4-                                                            chloro-quinoline                                                          43  2-Trichloromethyl-8-                                                                             7             78.3                                         trifluoromethyl-4-                                                            chloro-quinoline                                                          44  2,6-bis-(Trichloromethyl)-                                                                       12            87.6                                         4-chloro-quinoline                                                        45  2,2'-bis-Trichloromethyl-                                                                        16            73.4                                         8,8'-dimethyl-4,4'-                                                           dichloro-6,6'-biquinoline                                                 46  2-Trifluoromethyl-4-                                                                             10            73.2                                         chloro-5-dichloromethyl-                                                      quinoline                                                                 47  2-Trifluoromethyl-4-                                                                             10            87.4                                         chloro-6-trichloromethyl-                                                     quinoline                                                                 48  2-Trifluoromethyl-4-                                                                             10            81.7                                         chloro-7-trichloro-                                                           methyl-quinoline                                                          49  2-Trifluoromethyl-4-                                                                             10            79.3                                         chloro-8-dichloromethyl-                                                      quinoline                                                                 50  2-Trifluoromethyl-4,5-                                                                           10            84.6                                         dichloro-8-trichloro-                                                         methyl-quinoline                                                          51  2-Trifluoromethyl-4-chloro-                                                                      10            67.3                                         8-trichloromethyl-                                                            quinoline                                                                 52  2-Trichloromethyl-4-chloro-                                                                      1             73.2                                         7-methyl-quinoline                                                        53  2-Trichloromethyl-4-chloro-                                                                      1             80.3                                         5-trifluoromethyl-                                                            quinoline                                                                 54  2-Trichloromethyl-4,5,7-                                                                         1             87.3                                         trichloro-quinoline                                                       55  2-Trichloromethyl-4,7,8-                                                                         1             72.1                                         trichloro-quinoline                                                       56  2-Trichloromethyl-4,6-                                                                           1             86.3                                         dichloro-8-methyl-quinoline                                               57  2-Trichloromethyl-4,7-                                                                           1             93.4                                         dichloro-8-methyl-quinoline                                               58  2-Trichloromethyl-4,5,8-                                                                         1             92.7                                         trichloro-quinoline                                                       59  2-Trichloromethyl-4,8-                                                                           1             73.7                                         dichloro-6-methyl-quinoline                                               60  2-dichloromethyl-4,8-                                                                            14            65.3                                         dichloro-6-methyl-quinoline                                               ______________________________________                                    

    __________________________________________________________________________    NMR data and melting point values of the compounds prepared according to      the examples                                                                  __________________________________________________________________________    R.sup.1                                                                            R.sup.6                                                                         X R.sup.3                                                                          R.sup.2                                                                            m.p. (°C.)                                                                   .sup.1 H--NMR data (ppm)                               __________________________________________________________________________    CCl.sub.3                                                                          H Cl                                                                              H  H    64-65 8.28 dd (J.sup.3 9.0Hz; J.sup.4 1.5 Hz 1H) and                                8.22 dd (J.sup.3 7.0 Hz; J.sup.4 1.5 Hz 1H) H (7                              and 8)                                                                        8.16 s(1H), H(3)                                                              7.86 ddd (J.sup.3 7.0 Hz; J.sup.3'  9.0 Hz;                                   J.sup.4 : 1.5 Hz 1H) and                                                      7.74 ddd (J.sup.3 7.0 Hz; J.sup.3'  9.0 Hz;                                   J.sup.4 : 1.5 Hz 1H) H (6 and 7)                       CCl.sub.3                                                                          Cl                                                                              Cl                                                                              H  H    130-133                                                                             8.27 dd (J.sup.3 8.0 Hz; J.sup.4 2.0 Hz 1H) and                               8.23 dd (J.sup.3 8.0 Hz; J.sup.4 2.0 Hz 1H) H (5                              and 8)                                                                        7.87 ddd (J.sup.3 8.0 Hz; J.sup.3'  7.0 Hz; 7.0 Hz                            1H) and                                                                       7.77 ddd (J.sup.3 8.0 Hz; J.sup.3'  7.0 Hz;                                   J.sup.4 7.0 Hz 1H) H (6 and 7)                         CCl.sub.3                                                                          H Cl                                                                              5Me                                                                              H    89-92 8.10 s (1H) H (3); 3.02 s (3H) methyl (5),                                    8.07 dd (1H); 7.70 dd (1H); 7.47 dd (1H); H (6-, 7                            and 8)                                                 CCl.sub.3                                                                          Cl                                                                              Cl                                                                              5Me                                                                              H    172-174                                                                             8.06 dd (J.sup.3 8.5 Hz; J.sup.4 1Hz 1H) and                                  7.56 dd (J.sup.3 8.0 Hz; J.sup.4 1Hz 1H) H (6 and                             8)                                                                            7.66 dd (J.sup.3 8.5 Hz; J.sup.3'  8.0 Hz 1H) H                               (7)                                                                           3.05 s (3H) methyl (5).                                CHCl.sub.2                                                                         Cl                                                                              Cl                                                                              5Me                                                                              H      140-142.5                                                                         8.07 dd (1H) and 7.47 dd (1H) H (6 and 8);                                    7.60 dd (1H) H (7); 7.30 s (1H) dichloromethyl H                              (2);                                                                          3.10 s (3H) methyl (5).                                CCl.sub.3                                                                          H Cl                                                                              6Me                                                                              H    85-88 8.12 s (1H) H (3); 8.10 d (J.sup.3 8.5 Hz, 1H)                                H (8); 8.00 dq (J.sup.4 0.9 Hz; J.sup.4'  2.0 Hz                              1H)                                                                           H (5); 7.70 dd (J.sup.3 8.5 Hz; J.sup.4 2.0 Hz 1H)                            H (7);                                                                        2.60 s (b) methyl (6).                                 CCl.sub.3                                                                          Cl                                                                              Cl                                                                              6Me                                                                              H    155-157                                                                             8.08 d (J.sup.3 8.0 Hz, 1H) H (8); 8.00 m (b)                                 (1H)                                                                          H (5); 7.67 dd (J.sup.3 8pHz, J.sup.4 2.0 Hz 1H) H                            (7);                                                                          2.65 s (3H) methyl (6).                                CHCl.sub.2                                                                         Cl                                                                              Cl                                                                              6Me                                                                              H    96-99 8.05 d (J.sup.3 8 Hz 1H) H (8); 7.90 m (1H)                                   H (5); 7.61 dd (J.sup.3 8.0 Hz, J.sup.4 1.9 Hz,                               1H) H (7);                                                                    7.30 s (1H) dichloromethyl H (2); 2.60 s (3H)                                 methyl (6).                                            CCl.sub.3                                                                          H Cl                                                                              7Me                                                                              H    82-83 8.13 d (J.sup.3 8.5 Hz 1H) H (5); 8.09 s (1H)                                 H (3); 8.00 s (b) (1H) H (8); 7.57 dd                                         (J.sup.3 8.5 Hz, J.sup.4 1.5 Hz 1H) H (6); 2.61 s                             (3H) methyl (7).                                       __________________________________________________________________________    R    R X R  R    m.p. (°C.)                                                                   .sup.1 H--NMR data (ppm)                               __________________________________________________________________________    CCl.sub.3                                                                          H Cl                                                                              8Me                                                                              H    104-106                                                                             8.14 s (1H) H (3); 8.08 dd (J.sup.3 8.5 Hz;                                   J.sup.4 1.5 Hz, 1H) H (5); 7.68 dm (1H)                                       H (7); 7.60 dd (J.sup.3 8.5 Hz; J.sup.3'  2.5 Hz;                             1H)                                                                           H (6); 2.87 s (3H) methyl (8).                         CHCl.sub.2                                                                         H Cl                                                                              8Me                                                                              H    104-107                                                                             8.10 dd (J.sup.3 8.0 Hz; J.sup.4 0.9 Hz, 1H ) H                               (5);                                                                          7.97 s (1H) H (3); 7.60 dd (J.sup.3 8.0 Hz;                                   J.sup.3'                                                                      7.6 Hz, 1H) H (6); 7.66 dm (J.sup.3 7.6 Hz, 1H)                               H (7), 6.85 s (1H) dichloromethyl H (2); 2.75 s                               (3H) methyl (8).                                       CH.sub.2 Cl                                                                        H Cl                                                                              8Me                                                                              H    69-72 8.08 dd (1H) H (5); 7.70 s (1H) H (3);                                        7.62 d (1H) H (7); 7.52 dd (1H) H (6);                                        4.85 s (2H) chloromethyl H; 2.80 s (3H) methyl                                (8)                                                    CCl.sub.3                                                                          H Cl                                                                              5CF.sub.3                                                                        H    44-45 8.44 dd (J.sup.3 9.0 Hz, J.sup.4 1 Hz, 1H) H (8);                             8.31 s                                                                        (1H) H (3); 8.23 d (b) (J.sup.3 7.5 Hz, 1H) H                                 (6);                                                                          7.87 dd (J.sup.3 9.0 Hz, J.sup.3'  7.5 Hz, 1H) H                              (7).                                                   __________________________________________________________________________    R.sup.1                                                                            R.sup.6                                                                         X R.sup.3                                                                          R.sup.2                                                                            m.p. (°C.)                                                                   .sup.1 H--NMR data (ppm)                               __________________________________________________________________________    CCl.sub.3                                                                          H Cl                                                                              6CF.sub.3                                                                        H    47-48 8.56 dq (J.sup.4 2.0 Hz; J.sup. 4.sub.F--H 0.9 Hz,                            1H) H (5);                                                                    8.35 dq (J.sup.3 9.0 Hz; J.sup.5.sub.F--H 0.6 Hz,                             1H) H (8);                                                                    8.25 s (1H) H (3); 8.03 dd (b) (J.sup.3 9.0 Hz;                               J.sup.4                                                                       7.0 Hz, 1H) H (7).                                     CCl.sub.3                                                                          H Cl                                                                              7CF.sub.3                                                                        H    72-74 8.55 dq (J.sup.4 1.8 Hz; J.sup.4.sub.F--H 0.9 Hz;                             1H) H (8);                                                                    8.39 dq (J.sup.3 9.0 Hz; J.sup.5.sub.F--H 0.8 Hz;                             1H) H (5);                                                                    8.27 s (1H) H (3); 7.96 dd (b) (J.sup.3 9.0 Hz;                               J.sup.4 1.8 Hz 1H) H (6).                              CCl.sub.3                                                                          H Cl                                                                              H  8CF.sub.3                                                                          88-90 8.50 dd (J.sup.3 8.5 Hz; J.sup.4 1.5 Hz, 1H) H                                (5);                                                                          8.28 s (1H) H (3); 8.24 d(b) (J.sup.3 8.5 Hz, 1H)                             H (7); 7.85 dd (J.sup.3 8.5 Hz; J.sup.3' : 8.5 Hz                             1H) H (6).                                             CCl.sub.3                                                                          H Cl                                                                              H  6Cl   99-101                                                                             8.24 d (j.sup.4 2.0 Hz; 1H) H (5); 8.18 s (1H) H                              (3);                                                                          8.17 d (J.sup.3 8.5 Hz; 1H) H (8); 7.78 dd                                    (J.sup.3 8.5 Hz J.sup.4 2.0 Hz; 1H                                            H (7).                                                 CCl.sub.3                                                                          Cl                                                                              Cl                                                                              H  6Cl  166-169                                                                             8.25 dd (J.sup.4 2.0 Hz; 0.5 Hz; 1H) H (5);                                   8.15 dd (J.sup.3 9.0 Hz; J.sup.5 0.5 Hz 1H) H                                 (8);                                                                          7.77 dd (J.sup.3 9.0 Hz; J.sup.4 2.0 Hz 1H) H                                 (7).                                                   CHCl.sub.2                                                                         Cl                                                                              Cl                                                                              H  6Cl  90-92 8.13 d (j.sup.4 1.5 Hz; 1H) H (5); 8.10 d                                     (J.sup.3                                                                      7.2 Hz, 1H) H (8); 7.72 dd (J.sup.3 7.2 Hz;                                   J.sup.4 1.5 Hz 1H) H (7); 7.35 s (1H) 2-dichloro-                             methyl H.                                              CCl.sub.3                                                                          H Cl                                                                              H  7Cl  82-84 8.25 dd (J.sup.4 2.0 Hz; J.sup.5 0.4 Hz; 1H) H                                (8);                                                                          8.20 d (b) (J.sup.3 9.0 Hz 1H) H (5); 8.15 s                                  (1H) H (3); 7.69 dd (J.sup.3 9.0 Hz; J.sup.4 2.0                              Hz; 1H)                                                                       H (6).                                                 CCl.sub.3                                                                          Cl                                                                              Cl                                                                              H  7Cl  144-146                                                                             8.23 d (J.sup.4 2.0 Hz, 1H) H (8); 8.14 d (J.sup.3                            9.0                                                                           Hz; 1H) H (5); 7.72 dd (J.sup.3 9.0 Hz; J.sup.4 2                             Hz;                                                                           1H) H (7).                                             CCl.sub.3                                                                          H Cl                                                                              H  8Cl  126-128                                                                             8.22 s (1H) H (3); 8.18 dd (J.sup.3 8.7 Hz;                                   J.sup.4 1.5 Hz 1H) H (5); 7.99 dd (J.sup.3 7.8                                Hz;                                                                           J.sup.4 1.5 Hz; 1H) H (7) 7.65 dd (J.sup.3 8.7                                Hz;                                                                           J.sup.3'  7.8 Hz 1H) H (6).                            __________________________________________________________________________    R    R X R  R    m.p. (°C.)                                                                   .sup.1 H--NMR data (ppm)                               __________________________________________________________________________    CCl.sub.3                                                                          Cl                                                                              Cl                                                                              H  6MeO 134-136                                                                             8.06 d (J.sup.3 9.0 Hz; 1H) H (8); 7.45 dd                                    (J.sup.3                                                                      9.0 Hz; J.sup.4 2.2 Hz; 1H) H (7); 7.40 d                                     (J.sup.4                                                                      2.2 Hz; 1H) H (5).                                     CCl.sub.3                                                                          H Cl                                                                              H  8MeO 148-151                                                                             8.18 s (1H) H (3); 7.81 dd (J.sup.3 8.85 Hz;                                  J.sup.4 1.3 Hz, 1H) H (5); 7.65 dd (J.sup.3 8.85                              Hz;                                                                           J.sup.3 7.75 Hz, 1H) H (6):, 7.18 dd (J.sup.3 7.75                            Hz;                                                                           J.sup.4 1.3 Hz, 1H) H (7); 4.12 s (3H) 8-methoxy                              H.                                                     CCl.sub.3                                                                          H Cl                                                                              5Cl                                                                              7Cl  130-133                                                                             8.19 d (J.sup.4 2.1 Hz, 1H) and 7.72 d (J.sup.4                               2.1 Hz;                                                                       1H) H (6 and 8); 8.16 s (1H) H (3).                    CCl.sub.3                                                                          H Cl                                                                              6Cl                                                                              8Cl  102-104                                                                             8.19 s (1H) H (3); 8.15 d (1H) and 7.90 (1H)                                  H (5 and 7).                                           CCl.sub.3                                                                          H Cl                                                                              5Cl                                                                              8Cl    123-124,5                                                                         8.23 s (1H) H (3); 7.83 d (J.sup.3 8.4 Hz; 1H)                                and                                                                           7.68 d (J.sup.3 8.4 Hz, 1H) H (6 and 7).               CCl.sub.3                                                                          H Cl                                                                              7Cl                                                                              8Cl  176-178                                                                             8.20 s (1H) H (3); 8.12 d (J.sup.3 9.0 Hz; 1H)                                and                                                                           7.77 d (J.sup.3 9.0 Hz; 1H) H (5 and 6).               CCl.sub.3                                                                          H Cl                                                                              5Cl                                                                              8Me  134-136                                                                             8.15 s (1H) H (3); 8.65 d (1H) and 7.55 d (1H)                                H (6 and 7); 280 s (3H) methyl (8).                    __________________________________________________________________________    R.sup.1                                                                            R.sup.6                                                                         X R.sup.3                                                                          R.sup.2                                                                            m.p. (°C.)                                                                   .sup.1 HNMR data (ppm)                                 __________________________________________________________________________    CCl.sub.3                                                                          H Cl                                                                              6Cl                                                                              8Me  123-125                                                                             8.15 s (1H) H (3); 8.10 d (J.sup.4 2.0 Hz, 1H)                                H (5); 7.65 m (1H) H (7); 2.83 s (3H) methyl (8).      CCl.sub.3                                                                          H Cl                                                                              7Cl                                                                              8Me    138-139.5                                                                         8.13 s (1H) H (3); 8.05 d (J.sup.3 9.0 Hz; 1H)                                and                                                                           7.70 d (J.sup.3 9.0 Hz, 1H) H (5 and 7);                                      2.92 s (3H) methyl (8).                                CCl.sub.3                                                                          H Cl                                                                              6Me                                                                              8Cl        8.17 s (1H) H (3); 7.93 d (J.sup.4 1.8 Hz; 1H)                                H (5); 7.80 d (1.8 Hz, 1H) H (7); 2.60 s (3H)                                 methyl (6)                                             CHCl.sub.2                                                                         H Cl                                                                              6Me                                                                              8Cl        8.03 s (1H) H (3); 7.93 d (J.sup.4 1.8 Hz, 1H)                                H (5); 7.75 d (J.sup.4 1.8 Hz, 1H) H (7);                                     6.90 s (1H) 2-dichloromethyl H; 2.58 s (3H)                                   6-methyl.                                              CCl.sub.3                                                                          H Cl                                                                              H  6CCl.sub.3                                                                         92-94 8.80-8.83 m (1H) H (5); 8.34-8.32 m (2H)                                      H (7 and 8); 8.25 s (1H) H (3)                         CCl.sub.3                                                                          H Cl                                                                              H  8CH.sub. 2 Cl                                                                      108-110                                                                             8.25 dd (J.sup.3 8.5 Hz; J.sup.4 1.5 Hz, 1H) and                              8.03                                                                          d (b) (J.sup.3 7.0 Hz; 1H) H (5 and 7); 7.65 dd                               (J.sup.3 7.0 Hz; J.sup.3'  8.5 Hz 1H) H (6); 5.45                             s (2H)                                                                        8-chloromethyl H.                                      CCl.sub.3                                                                          H Cl                                                                              H  8CHCl.sub.2                                                                        95-97 8.45 dd (1H) and 8.35 dd (1H) H (5 and 7);                                    8.225 s (1H) and 8.22 s (1H) 3- and 8-dichloro-                               methyl H; 7.85 dd (1H) H (6).                          CCl.sub.3                                                                          H Cl                                                                              H  8CCl.sub.3                                                                         134-136                                                                             8.58 dd (J.sup.3 7.5 Hz, J.sup.4 1Hz, 1H) and 8.44                            dd                                                                            (J.sup.3 9.0 Hz; J.sup.4 1.0 Hz, 1H) H (5 and 7);                             8.24 s (1H) H (3); 7.75 dd (J.sup.3 9.0 Hz,                                   J.sup.3 7.5 Hz; 1 H) H (6).                            __________________________________________________________________________

Remarks

Melting points are disclosed without correction NMR spectra were takenin CDCl₃ The decimal values were estimated. Tetramethylsilane was usedas reference

Abbreviations

s singlet

d doublet

t triplet

q quartet

m multiplet

b broad sign

J^(x) coupling constant;

x represents the bonds through which coupling is effected;

heteronuclear coupling is indicated in sub-index e.g. F-H meansfluoro-hydrogen coupling.

Antimicrobic Activity

The antimicrobic activity of the compounds of invention was tested infollowing microorganisms: Bacillus subtilis, E. coli, Proteus vulgaris,Salmonella thyphi murium, Streptococcus faecalis, Staphylococcus aureus,Aspergillus niger, Aspergillus fumigatus, Candida albicans,Saccharomyces cerevisiae, Trichophyton mentagrophytes.

2% bouillon solidified with agar-agar, and Sabouraud-glucosepepton wereused as culture-medium.

The test compounds were dissolved in concentrated DMSO whereupon 0.1 mlof the solution was taken in the culture-medium cooled to a temperatureof 40° C., the final pH of the culture medium was 7.4.

The dishes were inoculated with 10⁶ cells/ml, then incubated in athermostat at 37° C. The evaluation was carried out on the third andseventh day. The cultures used for control were prepared at the sametime quite identically as above but without any active agent.

Evaluation

A weak antifungoid activity was shown by the compounds of formula (I).The minimum inhibitory concentrations were measured between 300 and 500μg/ml.

Antiphlogistic and Analgesic Activity

The antiphlogistic activity was measured by testing the inhibition ofthe paw oedema (Winter, C. A. et al. J. Pharmacol Exp. Ther 141 369(1963)).

The analgesic effect was tested by the inhibition of writhing syndromeprovoked by 3% acetic acid (Collier, H. et al. British J. Pharmacol.Chemother. 32, 295 (1968)).

The activity of acetylsalicylic acid and phenylbutazone were used asreference in above tests.

    ______________________________________                                        Compounds of formula (I)                                                      wherein R.sup.1 = CCl.sub.3 ; R.sup.6 = H;                                                             Inhibition of                                                                            Analgetic                                 X = Cl and       Dose    carrageenan                                                                              activity                                  R.sup.2     R.sup.3  i.p.    oedema (%)                                                                             (%)                                     ______________________________________                                        8-MeO       H        100     65       100                                     8-Me        H        100     61       60                                      8CCl.sub.3  H        100     50       60                                      5Cl         8-Me     100     47       100                                     6CF.sub.3   H        100     33       80                                      6MeO        H         50     25       60                                      8CF.sub.3   H        100     --       40                                      6Me         H        100     --       40                                      8CHCl.sub.2 H        100     --       40                                      Acetylsalicylic acid                                                                           100     71         60                                        Phenylbutazone   100     65         20                                        ______________________________________                                    

What is claimed is:
 1. A chlorinated quinoline derivative of formula (I)##STR14## wherein R¹ is --CCl₃, --CF₃, --CHCl₂ or --CH₂ Cl,R² ishydrogen when R³ is not hydrogen, or is halogen, C₁₋₄ alkoxy, C₁₋₄ alkylor R¹, R³ is hydrogen when R² is not hydrogen or is halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy or CF₃, R⁶ is hydrogen or halogen, and X is halogen.
 2. Acompound of the Formula (I) ##STR15## wherein R² is halogen, C₁ -C₄alkoxy, C₁ -C₄ alkyl, CCl₃, CF₃, CHCl₂ or CH₂ Cl; andR³ is hydrogen orC₁ -C₄ alkyl.
 3. 2-trichloromethyl-8-methoxy-4-chloro-quinoline asdefined in claim
 2. 4. 2-trichloromethyl-8-methyl-4-chloro-quinoline asdefined in claim
 2. 5. 2,8-bis-trichloromethyl-4-chloro-quinoline asdefined in claim
 2. 6. 4,5-dichloro-2-trichloromethyl-8-methyl-quinolineas defined in claim
 3. 7.2-trichloromethyl-6-trifluoromethyl-4-chloro-quinoline as defined inclaim
 2. 8. 2-trichloromethyl-6-methoxy-4-chloro-quinoline as defined inclaim
 2. 9. 2-trichloromethyl-8-trifluoromethyl-4-chloro-quinoline asdefined in claim
 2. 10. 2-trichloromethyl-6-methyl-4-chloro-quinoline asdefined in claim
 2. 11.2-trichloromethyl-8-dichloromethyl-4-chloro-quinoline as defined inclaim
 2. 12. A pharmaceutical composition which comprises as activeingredient a pharmaceutically effective amount of a compound of theFormula (I) as defined in claim 1 in admixture with a pharmaceuticallyacceptable inert carrier.
 13. A pharmaceutical composition whichcomprises as active ingredient a pharmaceutically effective amount of acompound of the Formula (I) as defined in claim 2 in admixture with apharmaceutically acceptable inert carrier.
 14. An analgesic method oftreatment which comprises the step of treating a susceptible subjectwith a therapeutically effective amount of the compound of the Formula(I) as defined in claim
 1. 15. An antiphlogistic method of treatmentwhich comprises the step of treating a susceptible subject with atherapeutically effective amount of the compound of the Formula (I) asdefined in claim
 1. 16. An antibacterial or antifungal method oftreatment which comprises the step of treating a susceptible subjectwith a therapeutically effective amount of the compound of the Formula(I) as defined in claim 1.